Immunotoxins, monoclonal antibodies or ligands, which are bound to a plant or bacterial toxin and specific for proteins overexpressed on the surface of cancer cells, have been studied intensively, especially on the possible use thereof as anti-cancer agents (Non-patent Document 1). A number of immunotoxins have been studied in preclinical tests and clinical tests, and the use of an interleukin-2-diphtheria toxin (IL2-DT; Ontak®, Eisai) for the treatment of cutaneous T-cell lymphoma (CTCL) has been approved by the U.S. Food and Drug Administration (FDA) (Non-patent Documents 2 and 3). In addition, Pseudomonas exotoxin-based immunotoxins including interleukin-4-Pseudomonas exotoxin [IL4 (38-37)-PE38 KDEL] and interleukin-13-Pseudomonas exotoxin (IL13-PE38QQR) are currently studied in clinical tests (Non-patent Documents 4 and 5). Diphtheria toxin and Pseudomonas exotoxin are both incorporated into lysosome, activated therein, translocated to cytosol, and acts by catalytically inactivating the elongation factor 2 in a ribosome complex. This mechanism of action allows efficient destruction of non-replicating tumor cells in the dormant state by the immunotoxins.
Although the approach of targeting cancer by using a bacterial toxin-based immunotoxin is attractive, there are restrictions due to the hepatotoxicity caused by the bacterial toxin and the immunogenicity induced by the toxin protein (Non-patent Documents 2, 4 and 6). Immunotoxins generally have a molecular size larger than that of compound or fragment antibody medicines and thus, may possibly interfere with efficient penetration of the medicine into the tumor mass in a human body. To overcome this problem, there exists an urgent need for a new-generation of immunotoxin with an advanced approach.
Hsp90 protein, one of the heat shock proteins, which is present widely in every cell, is one of the important proteins essential for regulation of cell function. Recently, because survivin, an anti-apoptosis protein (inhibiting apoptosis of cells) expressed in a large amount in cancer cells, is folded correctly by the Hsp90 and thus exerts its function, studies on geldanamycin, a compound showing an anti-cancer action by inhibition of the Hsp90 activity, are widely reported. However, the inhibition of protein function by the compound is inevitably associated with side effects, because the compound is stable in cells and thus can possibly cause functional disorders in normal cells.
Because Hsp90 is also found in normal cells in large amounts, an Hsp90 inhibitor may also show its action in normal cells, thereby causing the problem of side effects. The toxicity of geldanamycin is not allowable, and the development is a derivative thereof that has an Hsp90 inhibitory effect similar to geldanamycin and with lower nephrotoxicity and hepatotoxicity, i.e., 17-allylaminogeldanamycin (17-AAG) (also called Tanespimycin).
A candidate anti-cancer agent called shepherdin was proposed for Hsp90 (Non-patent Documents 7 and 8). However, shepherdin directly inhibits the binding between survivin and Hsp90 and leads to destabilization of the protein to be bound and the like and thereby disabling the inherent function by contact thereof with the ATP pocket, but the in vivo effect thereof cannot be said to be effective. In addition, there are still problems that require room for improvement even if the in vitro results are taken into consideration.
Thus, there exists a need in the art for the design of an anti-cancer agent with a new structure that is highly selective to cancer cells and effective also in vitro.
There is also a need in the art for development of a novel Hsp-targeted medicine.